Possible Involvement of the Autonomic Nervous System in Cervical

Matsui et al. BMC Musculoskeletal Disorders (2021) 22:419 https://doi.org/10.1186/s12891-021-04293-7

RESEARCH ARTICLE Open Access Possible involvement of the autonomic nervous system in cervical muscles of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) Takayoshi Matsui1,2, Kazuhiro Hara2, Makoto Iwata1, Shuntaro Hojo1, Nobuyuki Shitara1, Yuzo Endo1, Hideoki Fukuoka1, Masaki Matsui2 and Hiroshi Kawaguchi1*

Abstract Background: Patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) sometimes present with stiffness of the cervical muscles. To investigate the pathophysiology of ME/CFS, this observational study compared patients with versus without recovery from ME/CFS through local modulation of the cervical muscles. Methods: Over a period of 11 years, a total of 1226 inpatients with ME/CFS who did not respond to outpatient care were enrolled in this study. All patients received daily cervical muscle physical therapy during hospitalization. Self-rated records documenting the presence or absence of ME/CFS, as well as the representative eight symptoms that frequently accompany it at admission and discharge, were compared. Pupil diameter was also measured to examine autonomic nervous system function involvement. Results: The recovery rate of ME/CFS after local therapy was 55.5%, and did not differ significantlybysex,agestrata,and hospitalization period. The recovery rates of the eight symptoms were variable (36.6–86.9%); however, those of ME/CFS in the symptom subpopulations were similar (52.3–55.8%). The recovery rates of all symptoms showed strong associations with that of ME/CFS (p < 0.001). The pupil diameter was more constricted in the ME/CFS-recovered patients than in the ME/CFS- unrecovered patients in the total population and the subpopulations stratified by sex, age, and hospitalization period. Conclusions: There was a strong association between the recovery of ME/CFS and other related whole-body symptoms. The recovery of ME/CFS may be partly linked to amelioration of the autonomic nervous system in the cervical muscles. Trial registration: UMIN000036634. Registered 1 May 2019 - Retrospectively registered. Keywords: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), Autonomic nervous system, Cervical muscle

* Correspondence: [email protected] 1Orthopaedics and Spine Department, Tokyo Neurological Center, Toranomon 4-1-17, Minato-ku, Tokyo 105-0001, Japan Full list of author information is available at the end of the article

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Background and low back pain [23, 24]. In contrast to the sympa- Myalgic encephalomyelitis / chronic fatigue syndrome thetic nervous system’s excitatory role under stressful (ME/CFS) is a serious, chronic, and complex disease that situations, the parasympathetic nervous system oversees occasionally affects the lives of patients due to debilitat- resting, recovery from stress, and maintenance of ing fatigue [1–4]. It is frequently accompanied by various homeostasis. Several nuclei of the hypothalamus gener- symptoms, such as headache, cervical stiffness, vertigo, ate coordinated patterns of responses of the two systems cardiovascular and gastrointestinal disorders, fever of to internal or social stressors [25]. The pupil light reflex unknown etiology, and psychological disorders. The high is known to be a representative indicator which can be prevalence and low employment rates of patients with used to evaluate autonomic nervous system function. In ME/CFS impose an enormous burden on society. The this reflex action, the constrictor muscle of the pupil de- Institute of Medicine of the National Academy of Sci- creases the diameter of the pupil under control of the ences reported that ME/CFS affects an estimated 2.5 ciliary ganglion, which is activated and innervated by a million people in the United States and generates direct preganglionic autonomic nerve fiber [26–28]. In a recent and indirect expenses of approximately $17–$24 billion study, the preliminary pupil light reflex test performed annually [5]. in a subpopulation, suggested possible autonomic ner- Since ME/CFS is a heterogeneous condition with a vous system dysfunction in the cervical muscles of pa- complex and multifactorial etiology, reaching a conclu- tients with whole-body symptoms [22]. sive diagnosis using the current methods is difficult. Al- To investigate the pathophysiology of ME/CFS, we though several studies have suggested the involvement performed the two cervical muscle physical therapies of abnormal widespread metabolites [6–8], infection and [18–20] in 1226 patients with ME/CFS and examined neurological disorders [9], calcium ion channels [10], or the relationships between ME/CFS recovery and the rep- anaerobic thresholds [11, 12]; the pathogenic mechanism resentative eight whole-body symptoms that frequently of ME/CFS remains unclear. As such, patients are diag- accompany it. Furthermore, to evaluate the possible in- nosed through the exclusion of other conditions that volvement of the autonomic nervous system as an could be responsible for the subjective symptoms with underlying causative mechanism, we also compared the abnormalities across many domains [13, 14]. Thus, treat- changes of the pupil diameters between patients who ment remains symptom-based, multidimensional, and showed ME/CFS recovery versus those who did not tailored to the needs of the individual patient [15, 16]. show ME/CFS recovery. In our clinical experience, we have observed a potential trend of indefinite whole-body symptoms including Methods ME/CFS occasionally coinciding with stiffness of the cer- Study design vical muscles, and have therefore proposed a new med- This study is an observational study which compared pa- ical concept called “cervical neuro-muscular syndrome” tients with versus without recovery from ME/CFS. [17]. For the treatment of the indefinite symptoms, we tried local modulation of the cervical muscles. Among Patients the physical therapies, low-frequency electrical stimula- Of the patients who visited our institutions between May tion [18, 19] and far-infrared irradiation [20] are report- 2006 and May 2017, and were diagnosed with ME/CFS ac- edly effective at treating stiffness of the cervical muscles. cording to Fukuda’sdefinition[13], we enrolled 1363 A previous study of patients with whiplash-associated patients who could not be successfully treated as outpa- disorders showed that the combined application of these tients, and were therefore hospitalized. Outpatient care two physical therapies to the cervical muscles amelio- was variable and included pharmacological and behavioral rated not only local symptoms in the neck and shoulder, strategies but did not include the application of physical but also indefinite symptoms in the whole body [21]. therapies to the cervical muscles. Hospitalization was de- Furthermore, a recent study of 1863 patients showed cided by consent between patients and physicians inde- that therapies applied to the cervical muscles signifi- pendently of the severity of ME/CFS. The main reasons cantly improved the indefinite whole-body symptoms in- for hospitalization were persistent symptoms that required cluding headache, cervical pain or stiffness, vertigo or more intensive treatments, as well as the need for detailed dizziness, palpitation, dazzling, nausea or stomachache, examinations of other organs. Recovery from ME/CFS fever of unknown etiology, and depression [22]. was also defined according to Fukuda’s diagnostic criteria We propose autonomic nervous system involvement [13], mainly by amelioration of chronic fatigue and ex- as an underlying causative mechanism. This system, haustion. Discharge was decided by consent between pa- which regulates the unconscious actions of the body via tients and physicians independent of the ME/CFS the sympathetic and parasympathetic nerves, reportedly recovery by the definition above [13], and was determined plays a role in myalgic disorders such as fibromyalgia mainly by considerable improvement of symptoms of ME/ Matsui et al. BMC Musculoskeletal Disorders (2021) 22:419 Page 3 of 9

CFS or related whole-body symptoms. Patients who were diameter was also measured at admission and discharge, hospitalized for 5–120 days were enrolled. using a binocular infrared pupilometer (Iriscoder Dual C10641; Hamamatsu Photonics, Shizuoka, Japan). Each Intervention patient provided informed consent. All patients underwent low-frequency electrical stimulation and far-infrared irradiation applied to the cervical Statistical analysis muscles for 15 min two or three times daily throughout Statistical analyses were performed using SPSS 16.0 J for the hospitalization period. No other treatments such as Windows. P values less than 0.05 were considered statis- medication, injection, external fixation, or cervical trac- tically significant; all reported p values were two-sided. tion were performed. A combination of silver spike point As the sample size (n = 1226) was sufficient, the central (SSP; Nihon Medix, Chiba, Japan) and pain topra (LCF- limit theorem could be applied to confirm that the data 30; Celcom, Inc., Fukuoka, Japan) was used for the low- were normally distributed and that violation of the nor- frequency electrical stimulation, while a CERAPIA 3300 mality assumption would not cause major problems (Nihon Medix, Chiba, Japan) was used for the far- [29]. Hence, the paired Student’s t-test was used to infrared ray irradiation. examine the difference in the number of symptoms at For all participants, the self-rated records on the medical admission versus discharge. The difference in the num- interview sheets documenting the presence or absence of ber of patients with each symptom between admission the representative eight symptoms that frequently accom- and discharge was evaluated using the chi-square test. pany ME/CFS [1–4], including headache, cervical pain or The unpaired t-test was used to compare means between stiffness, vertigo or dizziness, palpitation, dazzling, nausea the recovered and unrecovered ME/CFS groups. In the or stomachache, fever of unknown etiology, and depres- univariate and multivariate logistic regression analyses, sion, were collected at admission and discharge. Pupil all variables were force entered into the multivariate

Fig. 1 Flowchart of participant enrollment and study design Matsui et al. BMC Musculoskeletal Disorders (2021) 22:419 Page 4 of 9

model. Forward stepwise multivariate logistic regression Relationship between ME/CFS recovery and eight related analyses were also performed. The best model was se- symptoms lected based on likelihood ratio tests. Among the representative eight symptoms accompanying ME/CFS [1–4], more than 70% of ME/CFS patients reported headache, cervical pain or stiffness, palpitation, Results dazzling, fever of unknown etiology, and depression; Flow and backgrounds of participants 43.1% reported vertigo or dizziness and 56.7% reported Figure 1 shows a flowchart of the patient enrollment nausea or stomachache (Table 2, the leftmost column). process of the present study. A total of 1363 patients The recovery rates of these symptoms in the total popu- who were diagnosed with ME/CFS according to the def- lation, after physical therapies administered during inition above [13] and hospitalized in our institutions hospitalization, were variable: more than 70% in patients were initially enrolled in this study. Of this group, 137 with vertigo or dizziness, nausea or stomachache, and were excluded after enrollment. This includes 42 who depression; 50–70% in patients with cervical pain or were discharged after less than 5 days; 14 who were hos- stiffness, palpitation, dazzling, and fever of unknown eti- pitalized for more than 120 days; 59 who were diagnosed ology; and 36.6% in patients with headache (Table 2, the with specific diseases in other organs after admission leftmost column). The recovery rates of ME/CFS among (one of whom died during hospitalization); seven who patients with the eight symptoms were similar (52.3– were transferred to other hospitals for treatment of spe- 55.8%) (Table 2, the second column from the left) to cific diseases; five who refused to undergo pupil diam- that of the total population (55.5%) (Table 1). Further- eter measurement; and 10 who discharged themselves more, the chi-square test (Table 2, the rightmost col- from the hospital based on their own judgement with umn) and logistic regression analyses (Table 3) between unknown reasons. After the removal of these patients the recovery versus non-recovery of these symptoms from the study population, 1226 completed the study clearly showed a strong association with ME/CFS recov- protocol. Of these patients, 680 (55.5%) were diagnosed ery in all symptoms (p < 0.001). Among the symptoms, as having recovered from ME/CFS at discharge, accord- recovery from depression was most strongly associated ing to the definition above [13], while 546 (44.5%) with ME/CFS recovery (odds ratio, 13.70; Table 3). remained unrecovered. The eight representative symptoms accompanying ME/CFS and the pupil diameters Pupil diameter test were assessed and compared between the ME/CFS-re- We also examined the possible involvement of autonomic covered and -unrecovered groups. nervous system function by comparing pupil diameters of Table 1 shows the baseline characteristics of the 1226 par- patients at admission and discharge (D-A) as well as the ticipants (448 men, 778 women) with a mean age of 46.4 ± change ratio adjusted by the diameter at admission ([D- 16.3 years (mean ± standard deviation) and a mean A]/A) (Table 4). In the total population, both change in hospitalization period of 62.5 ± 26.4 days. The recovery rate pupil diameter (D-A = − 0.046 ± 0.633 mm; mean ± stand- was not significantly altered by sex (men versus women), age ard deviation) and change ratio ([D-A]/A = − 0.002 ± strata (10–49 versus 50–89 years), or hospitalization period 0.123) decreased during hospitalization, suggesting that (5–60 versus 61–120 days) (p >0.05). the physical therapies had contributed to improved autonomic nervous system function. These decreases were Table 1 Baseline characteristics of study participants with versus strongly evident in ME/CFS recovered patients (D-A = − without recovery 0.099 ± 0.700 mm, [D-A]/A = − 0.011 ± 0.134). However, Variables Number (%) Number (%) Number (%) P- there were no decreases, but rather increases, in the unre- value Total Recovered Unrecovered covered patients (D-A = 0.020 ± 0.532 mm, [D-A]/A = 1226 (100.0) 680 (55.5) 546 (45.5) 0.009 ± 0.107). A statistical analysis of the total population Sex revealed a significant difference in the change in pupil diameter between the recovered and unrecovered groups Men 448 (36.5) 252 (56.3) 196 (43.7) 0.675 (p =0.001forD-A,andp = 0.007 for [D-A]/A), suggesting Women 778 (63.4) 428 (55.0) 350 (45.0) an association between autonomic nervous system func- Age strata (years old) tion and ME/CFS recovery. 10–49 736 (60.0) 408 (55.3) 328 (44.7) 0.979 In subgroup analyses stratified by sex (men versus 50–89 490 (40.0) 272 (55.5) 218 (44.5) women), age strata (10–49 versus 50–89 years), and – – Hospitalization period (days) hospitalization period (5 60 versus 61 120 days), the decreases were reproducible in all subgroups except for the 5–60 518 (42.3) 276 (53.3) 242 (46.7) 0.188 longer hospitalization (61–120 days) group in D-A 61–120 708 (57.7) 404 (57.1) 304 (42.9) (Table 4, the second column from the right), as well as Matsui et al. BMC Musculoskeletal Disorders (2021) 22:419 Page 5 of 9

Table 2 Number (percentage) of patients with versus without recovery according to the representative eight symptoms accompanying ME/CFS Total (n = 1226) ME/CFS recovered ME/CFS unrecovered P-value Headache 1162 (94.8) 648 (55.8) 514 (44.2) < 0.001 Recovered 425 (36.6) 314 (73.9) 111 (26.1) Unrecovered 737 (63.4) 334 (45.3) 403 (54.7) Cervical pain or stiffness 1071 (87.4) 583 (54.4) 488 (45.6) < 0.001 Recovered 606 (56.6) 414 (68.3) 192 (31.7) Unrecovered 465 (43.4) 169 (36.3) 296 (63.7) Vertigo or dizziness 528 (43.1) 285 (54.0) 243 (46.0) < 0.001 Recovered 459 (86.9) 272 (59.3) 187 (40.7) Unrecovered 69 (13.1) 13 (18.8) 56 (81.2) Palpitation 960 (78.3) 502 (52.3) 458 (47.7) < 0.001 Recovered 595 (62.0) 376 (63.2) 219 (36.8) Unrecovered 365 (38.0) 126 (34.5) 239 (65.5) Dazzling 979 (79.9) 536 (54.7) 443 (45.3) < 0.001 Recovered 513 (52.4) 341 (66.5) 172 (33.5) Unrecovered 466 (47.6) 195 (41.8) 271 (58.2) Nausea or stomachache 695 (56.7) 378 (54.4) 317 (45.6) < 0.001 Recovered 508 (73.1) 323 (63.6) 185 (36.4) Unrecovered 187 (26.9) 55 (29.4) 132 (70.6) Fever of unknown etiology 1045 (85.2) 554 (53.0) 491 (47.0) < 0.001 Recovered 663 Z(63.4) 479 (72.2) 184 (27.8) Unrecovered 382 (36.6) 75 (19.6) 307 (80.4) Depression 894 (72.9) 470 (52.6) 424 (47.4) < 0.001 Recovered 733 (82.0) 453 (61.8) 280 (38.2) Unrecovered 161 (18.0) 17 (10.6) 144 (89.4) the women, the younger generation (10–49 years) and with ME/CFS. However, whether the cervical muscle is a the longer hospitalization (61–120 days) groups in (D- possible target for treatment of ME/CFS remains un- A)/A (Table 4, the rightmost column). clear. In fact, the recovery rate of cervical pain or stiffness following the physical therapy was lower (56.6%) Discussion than that of other symptoms such as vertigo or dizziness, This study has shown that local therapy to the cervical nausea or stomachache, and depression (> 70%) (Table muscles led to recovery in more than half of patients 2, the leftmost column), suggesting that the mechanisms underlying the effect of the therapy might be other than Table 3 Odds ratio (95% CI) of the recovery (vs. non-recovery) direct modulation of the cervical muscles. The logistic of each symptom to that of ME/CFS by logistic regression regression analysis also showed that the odds ratio for analysis the recovery of cervical pain or stiffness was lower than P n Odds ratio 95% CI -value that of other symptoms, with that of depression being Headache 1162 3.41 2.63–4.43 < 0.001 the highest (Table 3). This is consistent with the treat- Cervical pain or stiffness 1071 3.78 2.92–4.87 < 0.001 ment response being due to psychological effects, rather Vertigo or dizziness 528 6.27 3.33–11.78 < 0.001 than physiological effects. However, whether depression Palpitation 960 3.26 2.48–4.28 < 0.001 is a cause or consequence of ME/CFS remains unclari- fied, as previously reported [1, 4]. It is possible that the Dazzling 979 2.76 2.13–3.57 < 0.001 physical therapy initially improves psychological disor- Nausea or stomachache 695 4.19 2.92–6.02 < 0.001 ders such as depression through the cerebral limbic sys- Fever of unknown etiology 1045 10.66 7.86–14.45 < 0.001 tem, which then leads to recovery of the hypothalamus Depression 894 13.70 8.11–23.15 < 0.001 coordination of responses to the sympathetic and para- CI confidence of interval sympathetic nervous systems [25]. Alternatively, the Matsui ta.BCMsuokltlDisorders Musculoskeletal BMC al. et

Table 4 Pupil Diameters (mm) at Admission and Discharge Total ME/CFS recovered ME/CFS unrecovered P- P- value value Admission Discharge D-A (D-A) / A Admission Discharge D-A (D-A) / A Admission Discharge D-A (D-A) / A D-A (D-A) (2021)22:419 /A Variables 5.440 5.394 -0.046 (0.633) -0.002 (0.123) 5.480 5.380 -0.099 (0.700) -0.011 (0.134) 5.391 5.411 0.020 (0.532) 0.009 0.001 0.007 (1.034) (1.050) (1.063) (1.076) (0.997) (1.017) (0.107) Sex Men 5.621 5.541 −0.080 −0.008 5.672 5.520 −0.152 − 0.019 5.555 5.567 0.013 (0.548) 0.007 0.005 0.015 (1.117) (1.089) (0.621) (0.114) (1.172) (1.110) (0.666) (0.119) (1.042) (1.064) (0.104) 5.336 5.310 −0.027 0.001 (0.129) 5.367 5.298 −0.068 −0.005 (0.142) 5.299 5.324 0.025 (0.523) 0.010 0.043 0.265 Women (0.969) (1.017) (0.640) (0.977) (1.047) (0.719) (0.960) (0.980) (0.109) Age strata (years old) 10–49 5.807 5.772 −0.035 0.001 (0.118) 5.853 5.764 −0.089 −0.008 (0.126) 5.750 5.782 0.032 (0.562) 0.011 0.010 0.029 (0.914) (0.901) (0.637) (0.949) (0.930) (0.687) (0.866) (0.865) (0.107) 50–89 4.889 4.827 −0.062 −0.006 4.920 4.806 −0.114 −0.015 (0.146) 4.850 4.853 0.003 (0.483) 0.005 0.040 0.101 (0.958) (1.001) (0.629) (0.131) (0.976) (1.024) (0.721) (0.937) (0.974) (0.109) Hospitalization period (days) 5–60 5.505 5.455 −0.050 −0.003 5.594 5.459 −0.135 −0.018 (0.117) 5.404 5.450 0.047 (0.501) 0.014 0.001 0.001 (1.044) (1.042) (0.606) (0.112) (1.085) (1.076) (0.674) (0.988) (1.005) (0.103) 61–120 5.393 5.349 −0.043 −0.001 5.401 5.326 −0.075 −0.005 (0.145) 5.381 5.380 −0.001 0.005 0.134 0.317 (1.025) (1.053) (0.653) (0.131) (1.041) (1.073) (0.717) (1.006) (1.027) (0.554) (0.111) mean (standard deviation) ae6o 9 of 6 Page Matsui et al. BMC Musculoskeletal Disorders (2021) 22:419 Page 7 of 9

effect of the present therapy could possibly be indirect vestibular nervous system. The cervicocollic and cervi- via concomitant central sensitization and/or myofascial coocular reflexes are afferent from the cervical muscles, trigger points of cervical soft tissues. It is also reported and involve the vestibular nucleus complex which is the that ME/CFS symptoms could be related to hypermobil- origin of the oculomotor nerve. Hence, the local therapy ity, intracranial hypertension, and craniocervical obstruc- to the cervical muscles might possibly improve the tions [30]. The present physical therapies, electrical oculomotor nerve function via the vestibular nervous stimulation and far-infrared irradiation, have also been system, and cause the amelioration of ME/CFS reported to stimulate nerve regeneration and repair [31, symptoms. 32], independently of direct muscle modulation. Further A limitation of the study is the use of Fukuda’s diag- studies using objective and quantitative measurements nostic criteria [13] which are soft outcome indicators of muscle stiffness, like the ultrasound elastography with subjective reports by patients. Although the criteria technique [33], may clarify whether the cervical muscle were most popular for the definition of ME/CFS at the is a possible target for treatment of ME/CFS. onset of this study (May 2006), at least in Japan, usage In this study, we measured pupil diameter without of the Canadian Consensus Criteria [41, 42], which is as- using a light stimulation as the indicator of autonomic sumed to be reliable and objective consensus diagnostic nervous function. However, pupil light reflex under light criteria, would have been more suitable for the defin- stimulation is known to be more sensitive than measur- ition. The cardiopulmonary exercise test methodology ing pupil diameter [26, 27], and has been used to test pa- for assessing fatigue and effort intolerance, which is a tients with clinical signs of autonomic nerve dysfunction representative symptom of ME/CFS [11, 12], would also such as those with Parkinson’s disease, Alzheimer’s dis- be an ideal tool for the definition. For the evaluation of ease, and diabetes mellitus [34–36]. Although this study the eight symptoms that frequently accompany ME/CFS initially aimed to measure pupil light reflex parameters as well, we used the self-rated records on the medical under light stimulation, such as constriction rate and interview sheets documenting only presence or absence, velocity, the institutional review board (IRB) did not which is subjective and qualitative. More quantitative allow us to deliver external stimulation that was not ap- variables with precise descriptions, such as a visual proved for the diagnosis or treatment of ME/CFS. How- analogue scale, would have led to more accurate results. ever, in a recent study on patients with indefinite The inpatient physical therapies performed in this symptoms throughout the body, a subpopulation ana- study, two or three times daily for a mean of 62.5 days, lysis of patients with dazzling exhibited a proportional are too costly for both health care providers and individ- improvement in the constriction rate and velocity of uals. The development of more simple and feasible treat- pupil diameter without stimulation by local therapies ments is the next task. For the modulation of cervical [22]. Hence, we assume that pupil diameter measured muscles, we previously performed a prospective trial of without light stimulation could represent the pupil light the effects of an oral muscle-relaxant on ME/CFS. While reflex parameters with stimulation as an indicator of the systemic modulation of muscle stiffness by the drug autonomic nervous system function. was somewhat effective at relieving local symptoms in The canonical pathway that regulates pupil diameter is the neck or shoulder, it had a minimal effect on whole- such that the ganglion cell axons project to the Edinger- body disorders including ME/CFS (unpublished observa- Westphal nucleus in the midbrain, where the pregangli- tion). Since we believe that local modulation of the cer- onic parasympathetic neuron fiber in the oculomotor vical muscles independent of physical or medical nerve is activated and commands the constrictor muscle intervention would effectively treat ME/CFS, we are now of the pupil [28]. Although the oculomotor nerve does not planning a prospective randomized controlled trial that pass through the cervical muscles, another non-canonical will examine the effects of a topical muscle-relaxant pathway via the afferent parasympathetic neuron fiber in poultice or ointment in patients with this disease. the vagus nerve, arising from the brainstem and extending through cervical muscles down to the thoracic and ab- Conclusions dominal viscera [37], may be involved in the regulation of Although the effect of local modulation of the cervical pupil diameter. Also, the sympathetic nerve reportedly en- muscles on ME/CFS remains unclear, there was a strong ters the orbit via the divisions of the trigeminal nerve and association between recoveries of ME/CFS and other re- a plexus of nerves surrounding the ophthalmic artery, a lated whole-body symptoms under the therapy. The re- part of which commands the constrictor muscle of the covery of ME/CFS may at least be partly through pupil as a long ciliary nerve [38, 39]. amelioration of the autonomic nervous system. A recent report showed that chronic vestibular multi- Abbreviations canalicular canalithiasis can be the trigger of symptoms ME/CFS: Myalgic encephalomyelitis / chronic fatigue syndrome; FIR: Far- in ME/CFS [40], suggesting the involvement of the infrared irradiation; IRB: Institutional review board; SSP: Silver spike point Matsui et al. BMC Musculoskeletal Disorders (2021) 22:419 Page 8 of 9

Acknowledgments 8. Mueller C, Lin JC, Sheriff S, Maudsley AA, Younger JW. Evidence of The authors thank Mrs. Hiroki Fujii and Ryuji Mashima at our institutions for widespread metabolite abnormalities in myalgic encephalomyelitis/chronic their invaluable technical assistance. fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging Behav. 2020;14(2):562–72. https://doi.org/10.1 Authors’ contributions 007/s11682-018-0029-4. TM and KH conceived of the study idea. TM, KH, MI, YE, NS, and HK started 9. Komaroff AL, Cho TA. Role of infection and neurologic dysfunction in the study. TM and HK obtained the ethical approval. TM, MI, YE, NS, SH, HF, chronic fatigue syndrome. Semin Neurol. 2011;31(03):325–37. https://doi. MM, and HK acquired the data. TM, KH, and HK interpreted the data. TM and org/10.1055/s-0031-1287654. HK performed the statistical analysis. TM and HK wrote the initial manuscript. 10. Cabanas H, Muraki K, Balinas C, Eaton-Fitch N, Staines D, Marshall-Gradisnik All authors revised the manuscript and approved the submitted version for S. Validation of impaired transient receptor potential melastatin 3 ion publication. channel activity in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients. Mol Med. 2019;25(1):14–28. https://doi.org/10.11 Funding 86/s10020-019-0083-4. There was no funding associated with this study. The patients were hospitalized 11. Stevens S, Snell C, Stevens J, Keller B, VanNess JM. Cardiopulmonary exercise for intensive treatment and detailed examination, but not for this study. The test methodology for assessing exertion intolerance in cost of treatment was borne partly by the patients and partly by the Japanese myalgicencephalomyelitis/chronic fatigue syndrome. Front Pediatr. 2018;6: national insurance. 242. https://doi.org/10.3389/fped.2018.00242. 12. 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